Sakano Masayoshi, Tomita Yoshinobu, Kanazawa Takumi, Ishibashi Sachiko, Ikeda Masumi, Oshita Haruna, Hananoi Yuri, Kato Yuki, Yamamoto Kurara, Furukawa Asuka, Kinoshita Mayumi, Haruki Shigeo, Tokunaga Masanori, Kinugasa Yusuke, Kurata Morito, Kitagawa Masanobu, Ohashi Kenichi, Yamamoto Kouhei
Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Front Oncol. 2024 Dec 11;14:1459940. doi: 10.3389/fonc.2024.1459940. eCollection 2024.
Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), is a leading cause of cancer-related death and has a poor prognosis. Despite the advancements in multidisciplinary therapies, resistance to conventional treatments warrants the development of novel therapeutic strategies. Ferroptosis, a form of cell death dependent on intracellular iron, has emerged as a potential mechanism for targeting cancer cells resistant to apoptosis. Guanosine triphosphate cyclohydrolase 1 (GCH1) has been identified as a novel antagonist of ferroptosis; however, its role in ESCC remains unclear. This study aimed to investigate the correlation between the expression and accumulation of the lipid peroxidation markers and regulators, including GCH1, in patients with ESCC and examined their prognostic significance. Furthermore, we investigated the relationship between lipid peroxidation regulators and cell death using an system to establish the basis for new therapeutic strategies.
We retrospectively analyzed 312 patients with ESCC who underwent radical esophagectomy at the Tokyo Medical and Dental University. Immunohistochemistry was performed to evaluate the expression of lipid peroxidation markers (4-hydroxy-2-nonenal) and regulators (glutathione peroxidase 4 [GPX4], ferroptosis suppressor protein 1 [FSP1], and GCH1). The correlation between these markers, clinicopathological features, and overall survival was assessed. experiments were performed using KYSE-150 cells to investigate the effects of GCH1 knockdown and overexpression on cell proliferation, cisplatin-induced cell death, and ferroptosis.
Low GCH1 expression was significantly associated with a poor prognosis in patients with ESCC. GCH1 expression correlated with lymph node metastases, vessel invasion, and the pathological tumor stage. , GCH1-knockdown cells exhibited increased proliferation and resistance to cisplatin-induced cell death, whereas GCH1 overexpression reduced cell proliferation. Simultaneous inhibition of GPX4 and FSP1 induced mild cell death; however, GCH1 knockdown dramatically enhanced ferroptosis, suggesting a synergistic effect.
GCH1 is a critical prognostic factor for ESCC and plays a significant role in the regulation of cell proliferation and ferroptosis. Targeting GCH1 in combination with GPX4 and FSP1 inhibitors may offer a novel therapeutic strategy for overcoming resistance in ESCC. Further studies are warranted to elucidate the involved molecular mechanisms and validate these findings .
食管癌，尤其是食管鳞状细胞癌（ESCC），是癌症相关死亡的主要原因，预后较差。尽管多学科治疗取得了进展，但对传统治疗的耐药性促使人们开发新的治疗策略。铁死亡是一种依赖细胞内铁的细胞死亡形式，已成为靶向抗凋亡癌细胞的潜在机制。鸟苷三磷酸环化水解酶1（GCH1）已被确定为铁死亡的新型拮抗剂；然而，其在ESCC中的作用仍不清楚。本研究旨在探讨ESCC患者脂质过氧化标志物和调节因子（包括GCH1）的表达与积累之间的相关性，并检验其预后意义。此外，我们使用一种系统研究脂质过氧化调节因子与细胞死亡之间的关系，为新的治疗策略奠定基础。
我们回顾性分析了东京医科齿科大学312例行根治性食管切除术的ESCC患者。采用免疫组织化学法评估脂质过氧化标志物（4-羟基壬烯醛）和调节因子（谷胱甘肽过氧化物酶4 [GPX4]、铁死亡抑制蛋白1 [FSP1]和GCH1）的表达。评估这些标志物与临床病理特征及总生存期之间的相关性。使用KYSE-150细胞进行实验，研究GCH1基因敲低和过表达对细胞增殖、顺铂诱导的细胞死亡和铁死亡的影响。
ESCC患者中GCH1低表达与预后不良显著相关。GCH1表达与淋巴结转移、血管侵犯及病理肿瘤分期相关。此外，GCH1基因敲低的细胞增殖增加且对顺铂诱导的细胞死亡具有抗性，而GCH1过表达则降低细胞增殖。同时抑制GPX4和FSP1可诱导轻度细胞死亡；然而，GCH1基因敲低显著增强了铁死亡，提示存在协同效应。
GCH1是ESCC的关键预后因素，在细胞增殖和铁死亡的调节中起重要作用。联合靶向GCH1与GPX4和FSP1抑制剂可能为克服ESCC耐药性提供一种新的治疗策略。有必要进一步研究以阐明相关分子机制并验证这些发现。
